Are protein-ligand complexes robust structures?

The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. While this is convenient from a design perspective, it ignores the fact that structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, any potential benefit of a rigid binding mode will have to be balanced against the entropic penalty that it entails. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Here we investigate a diverse set of 77 drug-like structures, focusing on hydrogen bonds as they have been described as essential for structural stability. We find that most ligands combine a single anchoring point with looser regions, thus balancing order and disorder. But some ligands appear untethered and may form fuzzy complexes, while others are completely constricted. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.

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